Ebook Diet And Colon Protein Kinase C
Colorectal cancer is the fourth most common cancer in the world today (WHO 1997). Its incidence rates vary approximately 20-fold around the world so that the high-risk areas include North America, Europe, and Australia, whereas Central and South America, Asia, and Africa are areas of low risk. In Finland, cancer of the colon and the rectum are the second and third most common cancers in women and men respectively (Finnish Cancer Registry 2000). The number of new cases per year has steadily increased since 1965, being now three times higher than in the mid 1960s. The incidence rates of colon cancer are currently increasing in all industrialised countries as well as in the urban areas of developing countries (WHO 1997).
The 20-fold international difference in colon cancer rates is generally explained by differences in dietary habits and other environmental factors. In their much referred report, Doll and Peto (1981) estimated that dietary factors may account for approximately 35% of cancer deaths, although the range of their estimate was wide from as low as 10% to as high as 70%. Since the early 1980s, a large body of evidence has emerged from epidemiological studies concerning the relationship between diet and colon cancer, which was recently reviewed by the expert panel of the World Cancer Research Fund (1997). The expert panel concluded that the most effective way of preventing colorectal cancer is consumption of diets high in vegetables and low in red and processed meat. Furthermore, consumption of diets high in non-starch polysaccharides (fibre), starch and carotenoids and low in fat, sugar, and eggs possibly decreases the risk of colon cancer (World Cancer Research Fund 1997).
Colon tumourigenesis is a multistep process affected by both environmental and genetic factors. Over the past two decades, the genetic events involved in the initiation and progression of colon cancer have been identified and a molecular model for colon tumourigenesis has been proposed (Fearon and Vogelstein 1990, Kinzler and Vogelstein 1996). This model is currently widely accepted to explain the development of the majority of colon tumours. According to this model, normal epithelium progress to hyperplasia, early to intermediate to late adenoma, carcinoma, and finally metastasis (Figure 1).
The driving force in the tumourigenic process is accumulation of mutations in key genes regulating cell growth, differentiation, and apoptosis, i.e. programmed cell death. These key genes can be classified into two major classes: the proto-oncogenes and the tumour-suppressor genes. Activating mutations in proto-oncogenes generate oncogenes that typically induce cell proliferation and thus abnormal growth. The most frequently mutated oncogene in colon cancer is the RAS gene. Tumour-suppressor genes are needed for cell growth arrest and apoptosis and therefore mutational inactivation of these genes leads to loss of negative growth control. Among the tumour-suppressor genes important in colon cancer are the adenomatous polyposis coli gene (APC), the deleted in colorectal carcinomas gene (DCC), and the p53 gene.
One of the major issues of current research is to understand how dietary factors interact with the genetic events to either enhance or suppress the tumourigenic process in the colon. Apart from carcinogens derived from environmental or cooking processes, diet as such is not likely to cause mutations in the key genes initiating colon carcinogenesis. However, the growth of both mutated and normal cells is regulated by different cell signalling pathways which may be either activated or suppressed by dietary constituents (Figure 1). One of these pathways consists of protein kinase C (PKC) isozymes which have been shown to be involved in colonic cell growth and differentiation as well as malignant transformation (Brasitus and Bissonnette 1998). Changes in PKC activity and isozyme expression are considered to occur at an early phase of colon carcinogenesis and therefore the dietary effects on PKC may be of importance. Cyclooxygenase-2 (COX-2) is generally recognised as perhaps even a more important contributor to colon carcinogenesis than PKC isozymes (Williams et al. 1997). However, changes in COX-2 expression and activity take place presumably somewhat later during the carcinogenic process when the possibilities of diet to modulate tumourigenesis are less promising. A number of other signal transduction pathways are likely to be involved in colon carcinogenesis.
The sphingomyelin pathway is particularly interesting since it is capable of inducing apoptosis and dietary sphingomyelin may have a specific role in regulation of this pathway in the colon (Duan 1998). Furthermore, the APC/?-catenin pathway is of major importance because mutations in the APC gene are the initiating events for a vast majority of both inherited and sporadic colon cancer cases (Kinzler and Vogelstein 1996). Mutations in the APC gene lead to epigenetic changes in other members of the pathway, ?-catenin in particular, and thus in proliferation, adhesion, and migration of intestinal epithelial cells (Pennisi 1998). There is also evidence that the APC/?- catenin pathway interacts with other cell signal pathways, for example with PKC isozymes (Murray et al. 1999).
CONTENTS
ABSTRACT
ABBREVIATIONS
LIST OF ORIGINAL PUBLICATIONS
1. INTRODUCTION
2. CELL SIGNAL TRANSDUCTION PATHWAYS RELATED TO COLON CANCER
- 2.1 Protein kinase C
2.2 Adenomatous polyposis coli/?-catenin
2.3 Sphingomyelinase
2.4 Cyclooxygenase
3. EPIDEMIOLOGICAL AND EXPERIMENTAL EVIDENCE ON DIET AND COLON CANCER
- 3.1 Fat
3.2 Red meat
3.3 Fibre rich foods
4. PROPOSED MECHANISMS OF FAT, RED MEAT AND FIBRE RICH FOODS IN COLON CARCINOGENESIS
- 4.1 Mechanisms related to fat
4.1.1 Bile acids and protein kinase C
4.1.2 Prostaglandin production
4.2 Mechanisms related to red meat
4.3 Mechanisms related to fibre rich foods
5. OBJECTIVES OF THE STUDY
6. STUDY DESIGNS AND METHODS
- 6.1 Study designs and diets
6.2 Animals and sample collection
6.3 Methods
7. RESULTS
- 7.1 Effects of fat, red meat, and fibre sources on colon signal transduction
in rats (I-V)
7.2 Effects of fat, red meat, and fibre sources on intestinal tumour
development in Min mice (VI)
8. DISCUSSION
- 8.1 Fat
8.2 Red meat
8.3 Fibre sources
9. CONCLUSIONS AND FUTURE PERSPECTIVES
10. ACKNOWLEDGEMENT
11. REFERENCES
ORIGINAL PUBLICATIONS
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